Aminoglycosides are potent bactericidal antibiotics, particularly active against aerobic, gram-negative bacteria and act synergistically against certain gram-positive organisms. Gentamicin is the most commonly used aminoglycoside, but amikacin may be particularly effective against resistant organisms. Aminoglycosides are used in the treatment of severe infections of the abdomen and urinary tract, as well as bacteremia and endocarditis. Aminoglycosides are poorly absorbed from the gastrointestinal tract. After parenteral administration, aminoglycosides are primarily distributed within the extracellular fluid. Penetration of biologic membranes is poor because of the drug's polar structure, and intracellular concentrations are usually low, with the exception of the proximal renal tubule; for review, see, Gonzalez et al., American Family Physician, Nov. 15, 1998; The Merck Manual of Diagnosis and Therapy, 1999, 17th Ed, Chap.153.
Hu (1998, PNAS 95, 9791–795) and Hu et al. (U.S. Pat. No. 6,482,802) report that neomycin was the only member of a panel of aminoglycoside antibiotics that was able to reduce angiogenin-induced cell proliferation and angiogenesis, as measured using cultured human endothelial cells and chick embryo chorioallantoic membranes (CAM). Streptomycin, kanamycin, gentamicin, amikacin, and paromomycin were found to lack anti-angiogenic activity. This Hu attributes to phospholipase C (PLC) inhibition because neomycin is the only aminoglycoside antibiotic of the panel tested that inhibits PLC, and because U-73122, another PLC inhibitor, similarly inhibited angiogenin-induced cell proliferation and angiogenesis. See abstract of Hu paper; col.20, lines 22–28, col.21, line 66–col.22, line 8, and col.27, lines 8–27 of Hu patent. The Hu patent also reports that injected neomycin was able to reduce growth of cultured angiogenin-secreting tumor cells (Olson et al., Int J Cancer. 2002 Apr. 20; 98:923–9; Clin Cancer Res. 2001 November;7:3598–605) transplanted into mice; see, col.27, line 43–col.29, line 10 of Hu patent.
From these findings, Hu suggests use of neomycin for treating any angiogenin-induced angiogenesis. The Hu patent purports applicability to all angiogenesis-related diseases, which are “myriad and varied” and “include, but are not limited to, various forms of neovascularization or hypervascularization diseases, inflammatory diseases, arthritis and cancer”, and then goes on to recite a laundry-list of all major solid and blood-borne tumors, corneal and retinal diseases, inflammatory diseases, and various infectious diseases, including AIDS (col.16, line 56–col.18, line 16). Among the 60+ recited solid tumors is colon cancer (col.17, lines 10–11).
Hu does not provide the public with any cure for cancer, inflammatory disease, arthritis, or AIDS. He has shown that neomycin can reduce angiogenin-induced angiogenesis and growth in CAM and cultured cell models, and from these data, claims to be able to treat innumerable human diseases. In fact, anti-angiogenesis drugs have notoriously failed to live up to their promise as cancer therapies, primarily because there are dozens of alternative factors which can drive angiogenesis. Science Journal, WSJ, Jul. 11, 2003. Furthermore, reports using azoxymethane (AOM) and 1,2-dimethyl hydrazine (DMH)-induced colon cancers have suggested neomycin is not a viable therapy for colon cancer, and may actually increase the incidence of colon adenocarcinomas (Reddy et al., 1984 JNCI 73, 275–9; Panda et al., 1999, Br J Cancer 80, 1132–6).
With the recent development of colon cancer animal models based on defined genetic lesions (e.g. Zhu et al., Cell 1998, 94, 703–714), the use of chemical carcinogenesis models like AOM and DMH has become less favored (Boivin et al., Gastroenterology 2003, 124, 762–777). Hence, a recent review of colon cancer chemoprevention surveys the many agents reported to influence intestinal tumors, and does not include any antibiotics; see, Table 1 of Corpet et al., Cancer Epidemiology, Biomakers & Prevention 2003, 12, 391–400. Work in colon cancer animal models has suggested that intestinal neoplasia is independent of gut microbial status (Dove et al., Cancer Res 1997, 57, 812–14).
The present inventors made the serendipitous discovery that enterically delivered aminoglycoside antibiotics can dramatically reduce the development of colorectal carcinogenesis in defined rodent models. The inventors here clinically extend these animal model findings by showing that enterically delivered aminoglycoside antibiotics can inhibit large bowel carcinogenesis in human patients with familial adenomatous polyposis. The inventors further extend these findings by showing that altering the population profile of gut flora, through a defined regimen of aminoglycoside antibiotic treatment and supplementation of non-target gut microbes such as Lactobacillus, is effective in preventing the formation of colorectal polyps and colorectal cancer. The inventors demonstrate prevention of spontaneous tumor formation indicating that the disclosed protocols interfere with early processes of carcinogenesis that are distinct from angiogenesis.